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Biomarcadores y Sepsis Ricard Ferrer Intensive Care Department Mutua Terrassa University Hospital Barcelona. SPAIN
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Transcript of Biomarcadores y Sepsis · 2015. 4. 18. · Differentiation between Sepsis and SIRS. S. Harbarth et...

  • Biomarcadores y Sepsis

    Ricard FerrerIntensive Care Department

    Mutua Terrassa University HospitalBarcelona. SPAIN

  • Reinhart Ket al. Clin. Microbiol. Rev. 2012;25:609-634

  • MARKER ANALYSISÿ Over 150 markers analyzed by immunoassay, including

    various pro-forms, variants, and fragments.

    Markers of :• Apoptosis

    (e.g., caspase-3)

    • Vasoregulation (e.g., BNP, proBNP, bigET-1, calcitonin)

    • Organ and tissue dysfunction (e.g., NGAL, myoglobin, I-FABP, pulmonary surfactant proteins)

    Markers of :• Pro-inflammation

    (e.g., CRP, TNFα, IL-1β, IL-8)

    • Anti-inflammation (e.g., IL-10, IL-6, soluble TNF receptors)

    • Coagulation and fibrinolysis (e.g., D-dimer, tissue factor, protein C)

  • UTILITY OF BIOMARKERS OF SEPSIS

    • Screening• Diagnosis and early recognition• Risk Stratification• Identify responders to therapy.• Monitoring of the Response to

    Therapy.

  • BIOMARKERS and CLINICAL DECISIONS

  • Biomarkers of infection

    • Single determination– value in the diagnosis of infection– Value in determining severity

    • Serial determinations– as predictor of infection– monitoring clinical course and response to

    antibiotic therapyPóvoa ICM 2002;28:235

  • Time course: Endotoxin Challenge

    Reinhardt K et. al. Crit Care Clin 22 2006 503-19

  • Which is the useful marker for the early recognition of sepsis?

    IL-6CRP

    PCTWBC

    TNF-α erythrocyte sedimentation

  • The Biomarker Response in Sepsis

    • Most commonly studied and correlated with outcomes– CRP– Pro-calcitonin (PCT)– IL-6– HMGB1– STREM1– Panels of Biomarkers

  • C-Reactive Protein (CRP)

    • CRP measurement is a rapid, reproducible and inexpensive.

    • Acute Phase Protein– The acute phase response accompanies

    inflammation. – Acute phase proteins are defined as those

    proteins whose plasma concentrations increase by at least 25 percent during inflammatory states

    – Changes in levels of acute phase proteins result from cytokines: IL-6, IL-8 effect on hepatocytes

  • CPRDiagnostic Marker of Infection

    CRP > 8.7 mg/dl Cut-off

    Sensivity 93.4%

    Specifity 86.1%

    AUC 0.93

    Positive LR 6.71

    Negative LR 0.008 Povoa Clin Microbial Infect 2005;11:101-108Sierra Intensive Care Med 2004;30:2038-2045

  • CRP as a marker of infection predictionday -5 to day 0

    Póvoa Critical Care 2006;10:R63

    days

    p

  • CRP as a marker of infection predictionday -5 to day 0

    Póvoa Critical Care 2006;10:R63

    1 - esp ecific id ad e

    1 ,0 0,7 5,5 0,2 50 ,0 0

    sens

    ibilid

    ade

    1 ,0 0

    ,7 5

    ,5 0

    ,2 5

    0 ,0 0

    Max daily Δ CPRAUC (day -5 to day 0)

    0.86 (95% CI: 0.75–0.93)

    maximum daily Δ CRP > 4.1 mg/dL Ë ICU-aquired infectionsensitivity 0.92 , specificity 0.71, LR+ 3.22, LR- 0.11

    N=63 pts (28 controls; 35 infected – documentation)

    sens

    itivi

    ty

    1-specificity

  • CRP

    Póvoa Clin Microbiol Infect 2005;11:101

    P=0.024; r2=0.12

    N=76 infected pts

    Differentiation between Sepsis and SIRS

  • PCR as a Marker of Severity of Sepsis

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    p c r = 7 . 0 0 + 1 . 0 5 * s oR - S q u a r e = 0 . 1 2

    r=0.34, r2=0.12

    p=0.004

    SOFA

    CRP

    (mg/

    dl)

    Póvoa Clin Microbiol Infect 2005;11:101

    Lobo Chest 2003;123:2043

    N=313 ICU ptsN=76 infected pts

  • PCR as a Marker of Severity of Sepsis

    area under the receiver operating characteristics curves

    Intensive Care Med (2009) 35:909–913

  • Infection 2008; 36: 213–219

    Response to initial antimicrobial therapy

  • PCR. Conclusion

    • Single determination could be useful in the diagnosis of infection.

    • Daily measurement of CRP is easy and inexpensive to perform, and can aid in:– diagnosis of sepsis– assessing response to antibiotic therapy.

    • Limited value in determining prognosis.

  • Procalcitonin (PCT)

    • PCT is a 13-kd propeptide of calcitonin. In healthy individuals, levels of PCT are below 0.1 ng/mL.

    • In patients with sepsis, PCT levels may increase up to 5000 to 10,000 times with calcitonin still in the normal range.

    • In contrast to the short half-life of calcitonin (10 minutes), the half-life of PCT is approximately 24 hours

  • Procalcitonin(PCT)

    T Cell monocyte/Mø

    Calcitonin m-RNAParenchymal cell(Lung, liver etc.)

    Golgi apparatus PCT

    inhibition stimulus

    Virus infection Bacterial infection

    Useful in the diagnosis of bacterial infection

    Synthesized in the thyroid C cells as a precursor of calcitonin

    Production ofINF-γ

    Production of inflammatory cytokine(TNF-α、IL-1、IL-6)

    http://ja.wikipedia.org/wiki/%E3%83%95%E3%82%A1%E3%82%A4%E3%83%AB:Macrophage.jpghttp://ja.wikipedia.org/wiki/%E3%83%95%E3%82%A1%E3%82%A4%E3%83%AB:Macrophage.jpg

  • Procalcitonin Level in Systemic Viral Infections is Considerably Lower

    Cuquemelle E et al. Intensive Care Med 2011

  • PCT improves the reliability of the clinical diagnosis of sepsis

    S. Harbarth et al. Am J Respir Crit Care Med 2001;164:396-402

    AUC=0.94 AUC=0.7

    7

    AUC=0.92

    AUC~0.7

    Patients with SIRSand suspicion of infection (n=78)

    Pattern calculation for ICU patients with SIRS with / without PCT on a clinical model

    PCT PCT

  • Differentiation between Sepsis and SIRS

    S. Harbarth et al. Am J Respir Crit Care Med 2001;164:396-402

    Plasma levels of PCT, IL-6 y IL-8

    Medical and surgical ICU pat. (n=78),with SIRS and suspicion of infection

  • Meta-Analyses

  • Procalcitonin as a diagnostic test for sepsis in critically ill adults and after

    surgery or trauma: A systematic review and meta-analysis.

    ÿ Global diagnostic OR for PCTÿ 2966 ptsÿ 25 studiesÿ 15.7 (9.1-27.1)ÿ Risk for positive PCT test in

    infected pts was 16-fold higher than in non-infected pts.

    ÿ Global diagnostic OR for CRPÿ 1322 Ptsÿ 15 studiesÿ 5.4 (3.2-9.2)

    ÿ Q* 0.78 vs. 0.71 p = .02

    Uzzan et al.

    Crit Care Med 2006; 34:1996–2003

  • Meta-analysis: Limitations

    ÿ Heterogeneity (Uzzan)ÿ Ageÿ Medical vs. SurgicalÿUzzan: No medical pts

    ÿ Co-morbiditiesÿ Underlying illnessÿCardiac surgery, peritonitis,

    meningitis, burns

    ÿ Single sample (Uzzan)ÿ Timing of sample

    ÿ Consecutive patientsÿ Publication biasÿ Negative studiesÿ Sample size

    ÿ Level of sepsisÿ Critically ill or not

    ÿ Diagnostic Accuracy of ORÿ 0-25: Test of little useÿ 25-100: intermediate valueÿ >100: excellent

    performance

    Tang B. Crit Care Med 2007

  • Accuracy of Procalcitonin for Sepsis Diagnosis in Critically Ill Patients:

    Systemic Review and Meta-Analysis

    Tang BM et al Lancet Infect Dis 2007;7:210-17

    Sensitivity and specificity: 71%(95% CI 67–76)AUC 0·78 (95% CI 0·73–0·83).

  • PCT CRP

  • Limitations

  • Charles PE et al Intensive Care Med 2006; 32: 1577-1583

    Retrospective study50 episodes of sepsis with positive blood culture: 15 candidemias (11 patients)

    and 35 bacteremias (33 patients)

    Procalcitonin depending on etiology

  • Severe trauma Meisner et al. Crit Care 2006 Burns Carsin et al. Burns 1997 Cardiogenic Shock Lecharny et al. CCM 2002Major surgery Meisner et al. Intensive Care Med 1998Pancreatitis Ammori et al. Pancreas 2003Heat stroke Nylen et al. Crit Care Med 1997

    Elevated procalcitonin without sepsis

  • Lack of a clear diagnostic cutoff

    Author Refer. N Estad PCT

    Harbarths S AJRCCM 2001 25 Median 21,3 (1,2-654)

    Giamarellos EJ ICM 2002 10 Mean 38,76 IC 0,15-77,38

    Claeys R CCM 2002 53 Median 5,9 (1,6-26,9)

    Clec´h R CCM 2004 62 Median 14 (0,3-767)

    Clec´h R CCM 2006 36 Median 8,40 (3,63-24,70)

    Cheval F ICM 2000 16 Mean 89 ± 154Brunkhorst FM ICM 2000 39 Mean 12,89 ± 4,39

    Procalcitonin in septic shock

  • Static vs. Dynamic Measurements

  • Biomarkers of infection prediction

    Castelli et al. Crit Care Med 2009

    INFE

    CTIO

    N

  • Survival & Concentration Changes over time for PCT and CRP after Multiple Trauma

    PCT

  • Procalcitonin. Conclusion

    ÿMeasurement of procalcitonin can aid in the diagnosis and stratification of sepsis.ÿSerial determinations could help in

    predicting sepsis and in determining prognosis.ÿSeveral limitations in sensitivity and

    specificity, and also cost.

  • IL-6: UtilityÿCytokines such as IL-6 and IL-8 of limited

    use clinically because of short half life and rapid receptor binding/antagonism

    ÿIL-6 and IL-8 levels are closely related to the severity of the physiologic response to infection and systemic inflammation.

    ÿThus, non-specific: elevated in major surgery, severe trauma, burns, autoimmune disorders, viral infection.

  • High-mobility group box 1 (HMGB1)ÿHMGB1 is released from myeloid cells

    exposed to lipopolysaccharide.ÿHMGB1 has delay kinetics and remains

    in the circulation for extended periods of time.ÿHMGB1 may be an important mediator

    and therapeutic target in sepsis and related conditions.

  • Intensive Care Med (2008) 34:1046–1053

  • Crit Care Med 2007; 35:1061–1067

  • Triggering receptor expressed on myeloid cells-1TREM-1

    Ventetoulo C and Levy M. Clin Chest Med 2008;29:591-603

    • Inmunoglobulin up-regulated in response to infection.• Soluble TREM-1 is shed from membranes of activated phagocitic cells and can be quantified.

  • N Engl J Med 2004;350:451-8.

    Independent predictors for diagnosing pneumonia

  • Crit Care Med 2005; 33:792–796

  • Crit Care Med 2009;37:96-104

    • Design: Prospective multicenter observational study.• Patients: 971 patients septic enrolled.• Nine biomarkers were assayed.• Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. • Derived formula for weighting biomarker values was used to calculate a “sepsis score”

  • Crit Care Med 2009;37:96-104

    BIOMARKER PANEL IN SEVERE SEPSIS

  • Crit Care Med 2009;37:96-104

    BIOMARKER PANEL IN SEVERE SEPSIS

  • MULTIVARIATE LOGISTIC REGRESSION AND SEPSIS SCORE

    Crit Care Med 2009;37:96-104

    Probability of severe sepsis:

  • Which is the useful marker for Risk Stratification of sepsis?

    IL-6CRP

    PCTsuPAR

    Preseptin

  • suPAR• Several studies have indicated that soluble urokinase-type

    plasminogen activator receptor (suPAR) concentrations may reflect the severity of infection and have reported that they are associated with a worse outcome

    Uusitalo-Seppälä R, et al. Intern Med 2012 Sep;272(3):247-56.

  • PRELIMINARY RESULTS

    • 36 patients. Age: 69 ± 18 years. Gender: 67% men. Mortality 17%.

    Significant variables were introduced in a linear regression model: only suPARmaintained statistical significance (p=0.02)

    The cutoff point for a specificity of 96%and sensitivity of 75% for suPAR was 6 ng/ml

  • soluble CD14 subtype (sCD14-ST)PRESEPTIN

    TLR4

    MD2

    LPSLBP

    mCD14

    Signal transduction

  • sCD14-STsCD14ST

    55

  • Produced from granulocytes.(PCT is from systemic organs and monocytes.)molecular weight :about 13kDaThe amino acid sequence:64 of the N-terminus of CD14Can not bind LPSNon biological activityHalf-life in blood:4-5hr (PCT:20-24hr)ÿ Blood level Increases 2hr after the onset of sepsis,

    reachs a peak in 3hr, and decreases in 4-8hrÿ IL-6 increases 3hr after the onset.

    sCD14-ST or Preseptin

  • • non-survivors

  • Which is the useful marker for Guiding Therapy of sepsis?

    IL-6CRP

    PCTEAA

    TNF-α

  • Biomarker guided antibiotic therapy

    Algorithm to assist in stopping antibiotics Algorithm to assist in stopping and starting antibiotics Algorithm to assist in starting and escalating antibiotics

  • PCT guidance in patients with severe sepsisand septic shock? (ProSEP study)

    Inclusion criteria

    • Patient suspected of severe sepsis or septic shock

    • Initiation of antibiotic therapy < 48hr

    Exclusion criteria

    • High-risk bacteria (P.aeruginosa, A.baumanii)

    • Infection known to require prolonged antibiotic therapy

    (e.g. endocarditis, deep abcesses, osteomyelitis)

    • Severe immune suppression/neutropenia

    Nobre et al. Am J Respir Crit Care Med 2008

  • Suspicion of severe sepsis orseptic shock*

    Antibiotic therapy

    PCT D1

    PCT D5

    • in non-complicated infections** and patient stable

    antibiotics

    PCT DxPCT decrease > 90% on Dx**

    antibiotics

    Cultures

    Stopping rules

    Daily PCT measurement

    PCT decrease > 90% on D5** PCT decrease < 90% on D5

  • % p

    atie

    nts

    with

    out

    antib

    iotic

    s

    n=68HR: 1.9 (1.2-3.1)p=0.009

    Probability to have antibiotics stopped

    Time to antibiotic discontinuation (days)

    PCT

    controls

    0 5 10 15 20

    0.00

    0.25

    0.50

    0.75

    1.00

    Nobre et al. Am J Respir Crit Care Med 2008

  • Control(n=37)

    PCT(n=31)

    p value

    28-day mortality 16.2% 16.1% 0.74

    Clinical cure 83.8% 90.3% 0.33

    Nosocomial infection 29.7% 22.6% 0.20

    Infection replase, % 2.7% 3.2% 0.70

    PCT-guided shortening of antibiotic treatmentduration does not affect outcome

  • Lancet 2010; 375: 463–74

    Overruling53%

    daily

  • 1315 patients assessed for eligibility685 ineligible158 had expected ICU stay 65104 had received AB for >24 hours99 required prolonged therapy63 not enrolled for logistic reasons46 had do-not-resuscitate orders31 were neutropenic15 had no medical insurance12 had been enrolled in other studies10 refused consent9 excluded for other reasons

    630 randomized

    311 assigned toProcalcitonin Group

    319 assigned toControl Group

    307 Included inanalysis

    (1 lost to follow-up on day 15)

    314 Included inanalysis

    (1 lost to follow-up on day 22)

    4 withdrew consent 1 randomized twice

    The ProRata Trial

    4 withdrew consent

    Bouadma et al. Lancet 2010

  • Allpatients

    VAP abdominalinfection

    UTI (+) Bloodcultures

    N

    CAP

    20 14

    9.9

    6.1

    10.6

    5.6

    9.4

    7.3

    10.8

    8.1

    14.5

    7.4

    12.8

    9.8

    0

    2

    4

    6

    8

    10

    12

    14

    16

    Dur

    atio

    n of

    trea

    tmen

    t (da

    ys)

    314 307 101 79 66 75 18 24 53 55

    PCT-guidedControl

    Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trial

    Bouadma et al. Lancet 2010

  • Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trial

    Pro

    bab

    ilit

    y of

    su

    rviv

    al,

    %

    Days after inclusion

    Procalcitonin (n=311)Control group (n=319)

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    0 10 20 30 40 50 60

    Bouadma et al. Lancet 2010

    p = n.s.

  • Matthaiou et al. Intensive Care Med 2012

    PCT guidance: duration of antibiotic therapy

  • Matthaiou et al. Intensive Care Med 2012

    28-day mortality, PCT guidance vs. control

  • Jensen J et al. Crit Care Med 2011; 39:2048 –2058

    A strategy with escalation of broadspectrum antimicrobials guided by daily procalcitonin measurements

    “Alert procalcitonin”:1. At baseline, PCT ≥ 1.0 ng/mL.2. PCT ≥ 1.0 ng/mL that was not decreasing at least 10% from the previous day.

    Overruling17.9%

  • Jensen J et al. Crit Care Med 2011; 39:2048 –2058

    P< 0.004

  • Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C).

    … no evidence demonstrates that this practice reduces the prevalence of antimicrobial resistance.

    … clinical experience with this strategy is limited and thepotential for harm remains a concern.

    Intensive Care Med Feb 2013Crit Care Med Feb 2013

  • Sepsis Trials: Precision Medicine

    • Use current knowledge to reduce the heterogeneity and noise.

    • Better genotype of sepsis: Pharmacogenomic approach.

    • Better phenotype of sepsis:– Theragnostic approach– Immunological status– Specific organ dysfunction

  • Man M et al. The Pharmacogenomics Journal (2012), 1-9

    Effect of Genetic Combination Markers on Response to treatment

  • Theragnostics

    • Treatment strategy for individual patients, that associates both a diagnostic test that identifies patients most likely to be helped or harmed by a new medication, and targeted drug therapy based on the test results.

    • The key application is identification of subgroups of patients presenting a profile likely to give a positive response to a given treatment.

  • EUPHRATES EUPHRATES77

    Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock

  • Polystyrene Fiber

    polymyxin B

    Endotoxin(green)

    Polymyxin B(red)

    Polymyxin B Immobilized Fiber Column:No systemic side effects since PMX does not enter circulation

  • Endotoxin

    JID 2004

  • What makes EUPHRATES unique?

    •Theranostic trialÿ biomarker positivity +clinical criteria

    required for enrollment•Blinded-device trial •Small number of highly productive sites •No SIRS criteria •Relatively small number of patients compared

    to other trials

    80

  • Patient selection - EAA™

    81

  • Am J Respir Crit Care Med Vol 180. pp 640–648, 2009

    Reduced mHLA-DR expression as a global biomarker of sepsis-associated immunosuppression

  • CCM 2013

    p= 0.17

    No major safety concerns

  • Protocol AP-recAP-AKI-02-01

    A Randomized, Double-Blind, Placebo-Controlled, Four-Arm, Parallel-Group, Proof of Concept, and Dose-Finding Adaptive Phase 2a/2b Study to Investigate the Safety, Tolerability

    and Efficacy and Effect on Quality of Life of Human Recombinant Alkaline Phosphatase in the Treatment of Patients With Sepsis-Associated Acute Kidney Injury

    Sepsis Trial Of alkaline Phosphatase in Acute Kidney Injury

    Protocol version 1.0_27May2014Study Notification Letter version 1.0_30Sep2014

    AM-PHARMA and PPD

    85

    http://www.am-pharma.com/http://www.am-pharma.com/

  • Conclusiones

    • Los biomarcadores complementan al juicio clínico en el diagnóstico y estratificación de riesgo en la sepsis.

    • Los algoritmos de decisión clínica que incluyen biomarcadores pueden tener utilidad para reducir el uso de ABX.

    • El fenotipado de cada episodio de sepsis mediante biomarcadores es un requisito en los nuevos estudios.

  • [email protected]

    Número de diapositiva 1Número de diapositiva 2MARKER ANALYSISUTILITY OF BIOMARKERS OF SEPSISNúmero de diapositiva 5Biomarkers of infectionTime course: Endotoxin ChallengeWhich is the useful marker for the early recognition of sepsis?The Biomarker Response in SepsisC-Reactive Protein (CRP)CPR�Diagnostic Marker of InfectionCRP as a marker of infection prediction�day -5 to day 0CRP as a marker of infection prediction�day -5 to day 0Número de diapositiva 14PCR as a Marker of Severity of SepsisPCR as a Marker of Severity of SepsisResponse to initial antimicrobial therapyPCR. ConclusionProcalcitonin (PCT)Número de diapositiva 20Procalcitonin Level in Systemic Viral Infections is Considerably LowerNúmero de diapositiva 23Número de diapositiva 24Meta-AnalysesProcalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: �A systematic review and meta-analysis. Meta-analysis: LimitationsAccuracy of Procalcitonin for Sepsis Diagnosis in Critically Ill Patients: �Systemic Review and Meta-AnalysisNúmero de diapositiva 30LimitationsNúmero de diapositiva 32Número de diapositiva 33Número de diapositiva 34Static vs. Dynamic MeasurementsBiomarkers of infection predictionNúmero de diapositiva 38Procalcitonin. ConclusionIL-6: UtilityHigh-mobility group box 1 (HMGB1)Número de diapositiva 42Número de diapositiva 43Triggering receptor expressed on myeloid cells-1�TREM-1Número de diapositiva 45Número de diapositiva 46Número de diapositiva 47Número de diapositiva 48Número de diapositiva 49MULTIVARIATE LOGISTIC REGRESSION �AND SEPSIS SCOREWhich is the useful marker for Risk Stratification of sepsis?suPARpreliminary resultssoluble CD14 subtype (sCD14-ST)�PRESEPTIN�sCD14-STsCD14-ST or PreseptinNúmero de diapositiva 57Which is the useful marker for Guiding Therapy of sepsis?Biomarker guided antibiotic therapyNúmero de diapositiva 60Número de diapositiva 61Número de diapositiva 62Número de diapositiva 63Número de diapositiva 64Número de diapositiva 65Número de diapositiva 66Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trialNúmero de diapositiva 68Número de diapositiva 69Número de diapositiva 70Número de diapositiva 71Número de diapositiva 72Número de diapositiva 73Sepsis Trials: Precision MedicineNúmero de diapositiva 75TheragnosticsNúmero de diapositiva 77Número de diapositiva 78Número de diapositiva 79What makes EUPHRATES unique? �Número de diapositiva 81Número de diapositiva 82Número de diapositiva 83Número de diapositiva 84Protocol AP-recAP-AKI-02-01ConclusionesNúmero de diapositiva 87